Within the CAM domain of biologically based therapies, soy and isoflavones play an increasing role. Potential benefits include prevention of cancer, heart disease, and menopausal symptoms. However, a few interventions with soy supplements warned about possible increases in cell proliferation and estrogenic activity in breast tissue. Given the health claims and the growing intake of soy foods and isoflavone supplements among healthy women and breast cancer survivors, it is urgent to investigate the potential adverse effects of soy, especially among survivors. The hypothesis for this project is that women with high soy intake throughout life show lower proliferation in breast tissue than women with low soy intake because they experienced a protective effect from soy since childhood. At the same time, we propose that women with high soy intake in adulthood and low soy intake early in life have greater proliferation in breast tissue than women with high soy intake throughout their life. The study will address the following specific aims: 1. Examine the relation between soy consumption at different times in life and markers of proliferation in normal and cancerous breast tissue among women with Caucasian and Japanese ancestry; 2. Determine whether regular soy intake exerts estrogenic effects on breast cells as assessed by progesterone receptor expression in normal and cancerous breast tissue; and 3. Explore the role of estrogen receptor Beta in the response of normal and cancerous breast tissue to soy intake. This investigation will include Japanese and Caucasian women from a nested case-control study on breast density, a substudy of a multi-ethnic cohort. Cohort members completed a validated food frequency questionnaire. The women in the nested case-control study also reported their lifetime soy history by stage of life. The tissue repository, part of the Hawaii Tumor Registry, has collected discarded pathologic materials, for approximately 85% of all cancer cases diagnosed in Hawaii during 1995 and is in the process of collecting specimens for consecutive years. Potential subjects will be recruited from 400 breast cancer cases diagnosed between 1995 and 1998 and their frequency-matched controls who reported a previous breast biopsy. Based on the 85% statewide coverage and an expected participation rate of 70%, we estimate that we can include neoplastic tissue for 240 breast cancer cases. Furthermore, we anticipate that normal breast tissue will be available in approximately 160 specimens from the women with breast cancer and from approximately 60 control women with previous biopsies. Tissue arrays will be prepared from paraffin-embedded tissue blocks using microarray technology. After histopathologic evaluation, we will perform histomorphometric measurements of the normal breast tissue. On the stained tissue arrays, we will examine two complementary markers of proliferation that work on paraffin blocks and decline little over time, Ki67 and PCNA. In addition, we will assess progesterone receptor expression as a marker of "estrogenic effect" on the breast and estrogen receptors Alpha and Beta as indicators of hormonal responsiveness. Multiple regression models with adjustment for potential confounders will be applied to explore the relation between histopathologic characteristics as the dependent variable with the different measures of soy intake as explanatory variables.